Current guidelines for the treatment of hypertension recommend an angiotensin receptor blocker (ARB) or an angiotensin-converting enzyme inhibitor (ACEI) as first- or second-line therapy according to subject characteristics and comorbid conditions (23).
ARBs lower the blood pressure of subjects with established hypertension or prehypertension (17). They reduce cardiovascular risk of stroke (51), myocardial infarction in heart failure (10, 26) and overall cardiovascular events in high risk individuals (20, 54) and improve coronary microcirculation and insulin resistance among subjects with hypertension and left ventricular hypertrophy (13). ARBs reduce proteinuria and slow the progressive loss of kidney function in subjects with nephropathy due to type 2 diabetes mellitus (7, 36). They are recommended as first- or second-line therapy for hypertension (8).
Among ARBs, telmisartan is distinguished by its lipophilicity, prolonged duration of action and additional activity as a peroxisome proliferator activated receptors gamma (PPARγ) agonist (5, 6, 14). The PPARγ activity of telmisartan is independent of its angiotensin type 1 receptor (AT1-R) blocking action (41). Candesartan also is a long-duration ARB but lacks significant PPARγ agonist action (41). Moreover, telmisartan is more effective than losartan in reducing proteinuria in a trial of subjects with diabetic nephropathy (4).
The limits of benefit by renin system intervention may have been reached with current ACEIs and ARBs because combination therapy does not appear to provide further protection against myocardial infarction and heart events and was achieved at the cost of increased adverse events (27, 54). However, antihypertensive therapy fails to abolish the cumulative risk of hypertension or cardiovascular disease, especially in elderly subjects, and those with comorbid conditions (1, 2). Moreover, a high salt intake that is characteristic of the modern diet reduces the antihypertensive and antiproteinuric effects of ACEIs or ARBs and thereby limits the potential of single agent therapies. This has spurred the search for other targets in addition to those directly stimulated through angiotensin II (Ang II) generation and activation of the AT1-R. These include enhanced signaling by endothelin type A and B receptors (18), adrenergic receptors (21, 22), thromboxane prostanoid receptors (47, 49) and diminished PPARγ activity (32). Of interest, all of these activating processes raise blood pressure (BP), engage oxidative stress and increase the generation of superoxide anion (O2.−) in animals and/or vascular smooth muscle cells in culture (32, 48). This provides a rationale for the use of an effective antioxidant to enhance the efficacy of drugs that block the renin-angiotensin-aldosterone (RAA) system.